This revised proposal requests continued support for a Comprehensive P60 Center to extend our study of antisocial drug dependence to encompass its implications for HIV/AIDS. The overall goal of this competitive renewal application is to contribute to our understanding of the etiology of individual differences in behavioral disinhibition, the relationship of this to drug abuse and the development of dependence, and the role that these play in the propensity for risky behaviors that may result in STDs, including HIV/AIDS. Our unique focus has been the contribution of genetics, both through linkage and association studies, and biometrical behavior genetic studies. Our overall thesis is that: Most new American HIV infections occur when adolescents or adults choose to engage in unprotected sexual behaviors or drug behaviors well known to be dangerous. Identifiable genes of some persons produce a lifelong behavioral disposition that involves excessive pursuit of exciting appetitive stimuli and unusual disregard of aversive consequences for behavior, a behavioral disinhibition. These characteristics frequently lead to substance abuse or dependence, antisocial behavior, and engagement in risky behaviors. Eventually, specification of the genetic and environmental factors influencing this behavioral disposition will lead to improved therapies that may reduce the vulnerability to engage in substance abuse, antisocial behavior, and risky behavior. In pursuit of this thesis we propose the following studies: 1) to identify specific genetic loci that influence behavioral disinhibition, we will conduct a genome-wide association study on an existing sample of 1000 adolescent cases and 1000 controls with Substance Dependence, Conduct Disorder, and HIV-related risk behaviors, and a newly ascertained sample of 600 adolescents recruited from adolescent substance abuse treatment programs and a control sample of 600 adolescents without serious substance or behavioral problems. 2) We will collect a third assessment in young adulthood on the clinical families and community family and twin samples participating in the Center, with detailed assessments of HIV risk behaviors. 3) We will conduct brain imaging studies to explore a neural basis for risky behaviors in disinhibited individuals, and explore the association of SNPs identified in '1' with activation of brain regions of interest, and 4) we will conduct a series of pilot studies of innovative approaches to the genetics of HIV risk behaviors. These projects will be supported by cores providing: A) Administrative, Educational, and Ethics support; B) Data management, informatics, and biostatistics; C) Genotyping and molecular genetics.